Process for the production of optically-active 4-amino-3-hydroxycarboxylic acids

ABSTRACT

Starting from 5-alkylidene or 5-benzylidenetetramic acid, optically-active 4-amino-3-hydroxy-carboxylic acids are produced in the (rel-3R,4R) configuration, especially statine. The synthesis process includes the O-acylation of the tetramic acid to the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optionally introduction of an amino protective group. Analogously the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids producible according to the invention are the structural elements of enzyme inhibitors.

BACKGROUND OF THE INVENTION

The invention relates to a process for the production ofoptically-active 4-amino-3-hydroxycarboxylic acids and their N-protectedderivatives.

The products of the process according to the invention have the generalformula: ##STR1## wherein R¹ is an optionally branched and/orsubstituted alkyl group with 1 to 10 C atoms or an optionallysubstituted aryl, arylalkyl or cycloalkyl group and X is a hydrogen oran amino protective group. These compounds have two chiral centers and,therefore, can occur in 4 stereoisomeric forms each.

The process according to the invention allows production alternativelyof the (3R,4R) or (3S,4S) enantiomer. These two enantiomers arecomprised by the stereochemical designations (rel-3R,4R) or (3R*,4R*).The first of the two designations is used below.

Some of these compounds, especially those with R¹ =isopropyl orcyclohexyl, are of interest as the structural element of peptides, whichhave enzyme inhibiting effects. But only the (3S,4S)-stereoisomer iseffective in this connection. Especially(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, known by the trivialname statine, which is contained in the renin inhibitor pepstatine,already was the aim of numerous different synthesis processes [see, forexample, European Patent No. 0210896; H. J. Altenbach. Nachr. Chem.Tech. Lab., 36, (1988), pages 756 to 758; M. Saiah et al., TetrahedronAsymmetry, 2, (1991), pages 111 and 112, as well as literature citedthere]. However, these syntheses are only poorly suitable or unsuitablefor the economical production of large amounts of different substituted4-amino-3-hydroxycarboxylic acids, because they require partly expensivestarting materials, partly are suitable only on a laboratory scale andpartly the necessary starting materials are available at all only forspecific radicals R¹ of general formula I.

BROAD DESCRIPTION OF THE INVENTION

The main object of the invention, therefore, is to provide a process forthe production of optically-active(rel-3R,4R)-4-amino-3-hydroxycarboxylic acids, that requires onlyreasonably priced starting materials and that can be performed on alarge scale. Other objects and advantages of the process and compoundsof the invention are set out herein or are obvious herefrom to oneskilled in the art.

The objects and advantages of the invention are achieved by the processand compounds of the invention.

The invention involves a process for the production of optically-active(rel-3R,4R)-4-amino-3-hydroxycarboxylic acids of the general formula:##STR2## wherein R¹ is an optionally branched and/or substituted alkylgroup with 1 to 10 C atoms or an optionally substituted aryl, arylalkylor cycloalkyl group and X is hydrogen or an amino protective group. Asubstituted tetramic acid of the general formula: ##STR3## wherein R¹has the above-mentioned meaning, is acylated with a carboxylic acid or acarboxylic acid derivative of the general formula: ##STR4## wherein R²is an optionally branched and/or substituted alkyl group with 1 to 10 Catoms or an aryl group and Y is halogen, OH or OC(═O)R², to a compoundof the general formula: ##STR5## Then the latter is stereoselectivelyhydrogenated to the corresponding enantiomeric pyrrolidin-2-ones of thegeneral formula: ##STR6## The (4R,5R)-enantiomer (Va) is hydrolyzedenantioselectively with a lipase to the corresponding(4R,5R)-4-hydroxypyrrolidin-2-one of the general formula: ##STR7## andseparated from the nonhydrolyzed (4S,5S)-enantiomer (Vb). Thenalternatively the acyloxy compound Vb or the hydroxy compound VI ishydrolyzed with cleavage of the lactam ring to the target compound I(X=H) and optionally converted (e.g., according to known processes) intothe corresponding N-protected form.

Preferably butyric acid or a derivative of butyric acid is used as thecarboxylic acid or carboxylic acid derivative (III), respectively.Preferably butyryl chloride is used as the butyric acid derivative.Preferably the stereoselective hydrogenation is performed with acatalyst of the group of palladium or rhodium catalysts or ofpalladium/rhodium mixed catalysts. Preferably a supported palladiumcatalyst is used as catalyst. Preferably a lipase from Candidacylindracea is used as the lipase. Preferably, after theenantioselective hydrolysis, the nonhydrolyzed (4S,5S)-enantiomer (Vb)is reacted to the target compound. Preferably after the cleavage of thelactam ring, the tert-butoxycarbonyl group is introduced as the aminoprotective group X. Preferably a 5-isobutylidene- (R¹ =isopropyl) or5-benzylidenetetramic acid-(R¹ =phenyl) is used as the substitutedtetramic acid (II).

The invention also includes (4S,5S)-4-acyloxypyrrolidin-2-ones of thegeneral formula: ##STR8## wherein R¹ is an optionally branched and/orsubstituted alkyl group with 1 to 10 C atoms or an optionallysubstituted aryl, arylalkyl or cycloalkyl group and R² is an optionallybranched and/or substituted alkyl group with 1 to 10 C atoms or anoptionally substituted aryl group. Preferably R¹ is isopropyl, phenyl orcyclohexyl. Preferably R² is propyl.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that, obtainable from 5-alkylidene tetramic acids ofthe general formula: ##STR9## or the tautomeric form: ##STR10## in whichR¹ has the above-mentioned meaning, and carboxylic acids or carboxylicacid derivatives of the general formula: ##STR11## in which R² is anoptionally branched and/or substituted alkyl group with 1 to 10 C atomsor an aryl group and Y is halogen, OH or OC(═O)R², 4-O-acyl-5-alkylidenetetramic acids of the general formula: ##STR12## wherein R¹ and R² havethe above-mentioned meanings, can be hydrogenated with goodstereoselectivity to a mixture, which consists basically of the(4RS,5RS)-racemate of the corresponding 4-acyloxy-pyrrolidin-2-ones ofthe general formula: ##STR13## wherein R¹ and R² have theabove-mentioned meanings and of small amounts of the corresponding(4RS,5SR)-racemate. The undesirable (4RS,5SR)-racemate can be easilyseparated.

Further it was found that the enantiomer with the (4R,5R)-configuration(Va) in the presence of lipases can be selectively deacylated. Becauseof the great difference in the polarity(4R,5R)-4-hydroxypyrrolidin-2-one of the general formula: ##STR14##wherein R¹ has the above-mentioned meaning, can be easily separated.

The unreacted (4S,5S)-4-acyloxypyrrolidin-2-one (Vb) can finally beconverted, analogously to known processes with cleavage of the acylgroup and opening of the lactam ring, to the corresponding(3S,4S)-4-amino-3-hydroxycarboxylic acid (I).

As an alternative to the above the corresponding(3R,4R)-4-amino-3-hydroxycarboxylic acid (I) can be obtained from(4R,5R)-4-hydroxypyrrolidin-2-one (VI), formed in the enzymaticdeacylation, after its isolation by hydrolytic opening of the lactamring.

The 5-alkylidenetetramic acids (II) necessary for the process accordingto the invention can be produced according to known processes from4-alkoxy-3-pyrrolin-2-ones and aldehydes (European Published PatentApplication No. 0358128).

It was found that their synthesis can be simplified significantly by theproduction of 4-alkoxy-3-pyrrolin-2-one and the reaction with aldehydebeing performed in one pot without isolation of the intermediateproducts. For this purpose an (E)-3-alkoxy-4-chlorobut-2-enoic acidalkyl ester, which is easily available from 4-chloroacetoacetyl chloride(European Published Patent Application No. 0346852), is cyclized withaqueous ammonia in a way known in the art (European Patent No. 0216324)to the corresponding 4-alkoxy-3-pyrrolin-2-one and the latter iscondensed without isolation in the presence of a strong base with thealdehyde to the corresponding 4-alkoxy-5-alkylidene-3-pyrrolin-2-one.Preferably (E)-4-chloro-3-methoxybut-2-ene methyl ester is used as theinitial material and sodium hydroxide as the strong base.

The thus-obtained 4-alkoxy-5-alkylidene-3-pyrrolin-2-one can beconverted without isolation in a way known in the art by acid hydrolysisinto 5-alkylidenetetramic acid (II).

For acylation of 5-alkylidenetetramic acid (II) to 4-acyloxy compounds(IV), which can be understood to be mixed anhydrides of thecorresponding carboxylic acids and tetramic acids or as enolic esters,basically every process for the production of mixed carboxylic acidanhydrides or carboxylic acid-enolic esters from the correspondingcarboxylic acids or carboxylic acid derivatives can be used. Thisincludes, for example, the reaction with the carboxylic acids in thepresence of carbodiimides or 1-acylimidazoles, the reaction withcarboxylic acid anhydrides or with carboxylic acid halides [see, H.Pielatzik et al. in "Methoden der Organischen Chemie" (Methods ofOrganic Chemistry), (Houben-Weyl), 4th ed., Vol. E5, Stuttgart (1985),pages 633 to 656, and G. Hesse in "Methoden der Organischen Chemie",(Houben-Weyl), 4th ed., Vol. VI/1d, Stuttgart, (1978), pages 108 to115].

A preferred embodiment uses carboxylic acid halides, especiallycarboxylic acid chlorides, in the presence of tertiary amines, such as,triethylamine or pyridine. Instead of free tetramic acids (II), theirenolates for example the sodium salts can also be used.

As carboxylic acids or carboxylic acid derivatives (III), aliphatic oraromatic carboxylic acids, especially C₂ -C₁₁ -alkanoic acids or benzoicacids, or their derivatives, can be used for the acylation, especiallypreferred is butyric acid or butyryl chloride.

The 4-acyloxy compounds (IV) were hydrogenated according to theinvention and two asymmetric centers were formed. The hydrogenationtakes place largely stereoselectively so that, aside from a little(4RS,5SR)-diastereomer, mainly the (racemic) (4RS,5RS)-pyrrolidin-2-one(Va/Vb) results.

As the catalyst for the hydrogenation, preferably a supported palladiumcatalyst is used, for example, 5 percent of palladium on activatedcarbon. Instead of palladium, rhodium, for example, rhodium on aluminumoxide, or a Pd/Rh-catalyst, can also be used. As the solvent for thehydrogenation, advantageously nonpolar or polar aprotic solvents, forexample, toluene, ethyl acetate or tetrahydrofuran, are used. Proticsolvents, such as, alcohols, can also be used but such lead to pooreryields. The hydrogenation is preferably performed at about roomtemperature and under medium pressure of, for example, 2 MPa (20 bar).

(4RS,5SR)-pyrrolidin-2-ones as well as hydrogenolysis productsoccasionally resulting as by-products in the hydrogention can easily beseparated in the working up, for example, by simple recrystallization inwhich they remain in the mother liquor.

The racemate from the (4R,5R)- and the (4S,5S)-pyrrolidin-2-one (Va/Vb)is enantioselectively deacylated according to the invention with anesterase. As the esterase a lipase is suitably used, preferably a lipasefrom Candida cylindracea. This lipase enantioselectively hydrolyzes the(4R,5R)-4-acyloxypyrrolidin-2-one (Va) to the corresponding 4-hydroxycompound. This deacylation is advantageously performed in an aqueousmedium at a pH near the neutral point, preferably at pH 6 to 8, tosuppress a non-enzymatic deacylation or hydrolysis. The temperature issuitably at 0° to 40° C., preferably at 0° to 25° C. During the reactionthe pH is maintained constant preferably by a suitable control unit("pH-Stat") by adding a strong base. As the strong base preferablysodium hydroxide solution is used. The reaction conversion can bedetermined by the amount of base added. Suitably the reaction isterminated after a conversion of about 50 percent of the total amountused (Va+Vb). Depending on whether the nonhydrolized or the hydrolizedenantiomer is to be processed further, the reaction advantageously isperformed up to a conversion of a little more than 50 percent orsomewhat less than 50 percent to obtain a product with the highestpossible optical purity.

The separation of the hydroxy compound (VI) from the acyloxy compound(Vb) is advantageously performed by extraction with a solvent of littlepolarity, for example, toluene. The hydroxy compound, in this caseremains in the aqueous phase, while the acyloxy compound changes intothe organic phase.

The optically active acyloxy compound or hydroxy compound producedaccording to the invention is finally converted analogously to knownprocesses (European Patent No. 0210896) by hydrolysis of the lactam ringand optionally of the ester function into the target compound.Preferably an acid is used as the catalyst for the acid hydrolysis,especially preferred is hydrobromic acid.

The unprotected 4-amino-3-hydroxycarboxylic acids tend towardspontaneous lactam formation and therefore advantageously are providedwith a protective group on the amino group. Such protective groups andthe methods for their introduction and removal are known to one skilledin the art; only the tert-butoxycarbonyl group is to be mentioned hereas an example. Instead of the amino group, the carboxyl group can alsobe protected, for example, by esterification.

The following examples illustrate the process according to theinvention.

EXAMPLE 1 (Z)-5-isobutylidene-4-methoxy-3-pyrrolin-2-one

120 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester wasinstilled in 200 ml of concentrated aqueous ammonia solution at 65° to70° C. with constant passing through of ammonia gas within 3 hours. Thereaction mixture was stirred another 1.5 hours at this temperature andthen refluxed another 0.5 hour. After cooling to room temperature, 450ml of 1M sodium hydroxide solution was added and the pH was brought togreater than 13 by the further addition of 33 percent sodium hydroxidesolution. Then 50 g of isobutyraldehyde was added and the reactionmixture was heated to 60° C. with stirring for 6 hours. After cooling toroom temperature, the precipitated product was filtered off, washed withcold water and dried in a vacuum drying cabinet. The yield of the titlecompound was 93.2 g (80 percent of theory). The title compound had amelting point of 140.5° to 141.1° C. (from diethyl ether).

EXAMPLE 2 (Z)-5-Isobutylidenepyrrolidine-2,4-dione (II, R¹ =isopropyl)

50 g of finely powdered (Z)-5-isobutylidene-4-methoxy-3-pyrroline-2-onewas stirred with 500 ml of concentrated hydrochloric acid for 5 hours atroom temperature. The mixture was then stirred 5 hours at roomtemperature and slowly mixed with 1 liter of 14 percent sodium hydroxidesolution. The precipitated yellow product was filtered off, washed withcold water and dried in a vacuum drying cabinet. The yield of the titlecompound was 42.0 g (92 percent of theory). The title compound had amelting point of 134° to 136° C. (THF/hexane).

EXAMPLE 3 (Z)-4-Butyryloxy-5-isobutylidene-3-pyrrolin-2-one (IV, R¹=isopropyl, R² =propyl)

31.8 g of (Z)-5-isobutylidenepyrrolidine-2,4-dione was suspended in 318ml of dichloromethane and cooled to -5° C. Then first 23.22 g of butyrylchloride was added and then 27.32 g of triethylamine was added. Afterthe addition the mixture was stirred another 10 minutes at 0° C., thendiluted with 100 ml of dichloromethane, and washed twice with 100 ml of5 percent NaHCO₃ solution each and twice with 100 ml of 0.4Mhydrochloric acid each. The aqueous phases were extracted separatelywith dichloromethane and the combined organic phases were dried onmagnesium sulfate. After the distilling off of the solvent, the crudeproduct (46 g) was recrystallized from hexane. The yield of the titlecompound was 38.8 g (84 percent of theory). The title compound had amelting point of 111° to 112° C. Other data concerning the titlecompound was:

¹ H-NMR (CDCl₃ ; 400 MHz): 1.03 (t, J=7.5, 3H), 1.12 (d, J=6.6, 6H),1.77 (m, 2H), 2.56 (t, J=7.5, 2H), 2.78-2.83 (m, 1H), 5.35 (d, J=10,1H), 6.15 (br.s, 1H), 9.91 (br.s, 1H).

EXAMPLE 4 (4RS,5RS)-4-Butyryloxy-5-isobutylpyrrolidin-2-one (Va/Vb, R¹=isopropyl, R₂ =propyl)

30.0 g of (Z)-4-butyryloxy-5-isobutylidene-3-pyrrolin-2-one (producedaccording to Example 3) was dissolved in 300 ml of toluene, mixed with3.0 g of palladium/activated carbon (5 percent of pf Pd) andhydrogenated for 24 hours in an autoclave at 2 MPa (20 bar). Then thecatalyst was filtered off, the filtrate was concentrated by evaporationand the residue was recrystallized from hexane. The yield of the titlecompound was 23.50 g (77 percent of theory). The title compound had amelting point of 101.5° to 102.7° C. Other data concerning the titlecompound was:

¹ H-NMR (CDCl₃ ; 400 MHz): 0.91-0.98 (m, 9H), 1.35-1.71 (m, 5H),2.29-2.36 (m, 3H), 2.71 (dd, J=6.4, 17.6, 1H), 3.88-3.93 (m, 1H),5.40-5.43 (m, 1H), 7.49 (br.s, 1H).

EXAMPLE 5 (4S,5S)-4-Butyryloxy-5-isobutylpyrrolidin-2-one (Vb, R¹=isopropyl, R² =propyl)

20 g of (4RS,5RS)-4-butyryloxy-5-isobutylpyrrolidin-2-one (producedaccording to Example 4) and 2 g of Candida cylindracea lipase(Biocatalysts) were stirred in 100 ml of water at room temperature. ThepH of the suspension was held constant at 7 by the addition of 1M sodiumhydroxide solution. After 70 hours and a consumption of 47.36 ml of 1Msodium hydroxide solution (corresponding to 53.8 percent conversion),the reaction was terminated. The reaction mixture was diluted with 200ml of water and extracted once with 400 ml and another two times with200 ml of toluene each. The combined toluene phases were concentrated byevaporation in a vacuum and the residue was dried in a high vacuum. Theyield of the title compound was 8.55 g (85.5 percent, relative to oneenantiomer). The title compound had a melting point of 94.9° to 95.3° C.Other data concerning the title compound was:

[α]_(D) ²⁰ : -3.9° (c=1.0; CHCl₃)

ee-value (GC, Lipodex® D-column) >99 percent

EXAMPLE 6 (3S,4S)-4-(tert-Butoxycarbonylamino-3-hydroxy-6-methylheptanoic acid (boc-Statine)(I, R¹ =isopropyl, X=tert-butoxy-carbonyl)

3.0 g of (4S,5S)-4-butyryloxy-5-isobutylpyrrolidin-2-one (producedaccording to Example 5) was stirred for 24 hours in 30 ml of 48 percentaqueous hydrobromic acid at 75° C. After cooling to room temperature,the mixture was diluted with 30 ml of water and was extracted threetimes with 20 ml of diethyl ether each to remove the butyric acid. Theaqueous phase was cooled to -10° C. and adjusted to pH 10 with 33percent sodium hydroxide solution. Then 20 ml of tetrahydrofuran and 2.9g of di-tert-butyl dicarbonate were added. The mixture was allowed toreact 94 hours at room temperature and the pH was held constant by theaddition of 1M NaOH. Then the mixture was acidified to pH 1.4 with 16percent hydrochloric acid and quickly extracted three times with 100 mlof diethyl ether each. The ether phase was dried on magnesium sulfateand concentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate/acetic acid6:4:0.1). The yield of the title compound was 2.09 g (58 percent oftheory). The title compound had a melting point of 120.2° to 120.9° C.(acetone/hexane). Other data concerning the title compound was:

[α]_(D) ²⁰ : -40.3° (c=1.0; CH₃ OH)

¹ H-NMR (d₆ -DMSO; 400 MHz): 0.83-0.88 (m, 6H), 1.22-1.29 (m, 2H), 1.38(s, 9H), 1.53-1.57 (m, 1H), 2.12 (dd, J=15.5, 9.1, 1H), 2.34 (dd,J=15.5, 3.8, 1H), 3.49-3.53 (m, 1H), 3.79-3.82 (m, 1H), 6.24 (d, J=9.1,1H).

EXAMPLE 7 (Z)-5-Benzylidene pyrrolidin-2,4-dione (II, R¹ =phenyl)

133 g of concentrated aqueous ammonia solution was heated to 65° to 70°C. 75 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester wasinstilled for 3 hours with constant passing through of ammonia gas. Themixture was stirred another 45 minutes at this temperature, heated 30minutes to reflux temperature and then cooled to room temperature. Afterthe addition of 300 ml of water and 50 ml of 33 percent sodium hydroxidesolution, 46.4 g of benzaldehyde was added. The mixture was heated for 6hours at 60° C. under stirring and then cooled to room temperature. Then688 ml of concentrated hydrochloric acid was added and the reactionmixture was stirred for 22 hours at 40° C. After cooling to roomtemperature, the yellow product was filtered off, washed with cold waterand dried in a vacuum drying cabinet. The yield of the title compoundwas 74.66 g (88 percent of theory). The title compound had a meltingpoint of 186° to 187° C. (THF/hexane).

EXAMPLE 8 (Z)-5-Benzylidene-4-butyryloxy-3-pyrrolin-2-one (IV, R¹=phenyl, R² =propyl)

To a suspension of 67.0 g of (Z)-5-benzylidene pyrrolidin-2,4-dionecooled to 0° C. in 670 ml of dichloromethane, 40.0 g of butyryl chlorideand then 47.1 g of triethyl amine were added and the mixture was stirredanother 5 minutes at 0° C. Then the mixture washed twice with 200 ml of5 percent NaHCO₃ solution each and then twice with 200 ml of 0.5Mhydrochloric acid each. The aqueous phases were extracted separatelywith dichloromethane. The combined organic phases were dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue was recrystallized from 230 ml of toluene. The yield of thetitle compound was 67.25 g (73 percent of theory). The title compoundhad a melting point of 139.8° to 141.5° C. Other data concerning thetitle compound was:

¹ H-NMR (CDCl₃ ; 400 MHz): 1.03 (t, J=7.4, 3H), 1.78 (m, 2H), 2.58 (t,J=6.7, 2H), 6.20 (s, 1H), 6.30 (s, 1H), 7.28-7.50 (m, 5H), 9.20 (br.s,1H).

EXAMPLE 9 (4RS,5RS)-5-Benzyl-4-butyryloxypyrrolidin-2-one (Va/Vb, R¹=phenyl, R² =propyl)

46.66 g of (Z)-5-benzylidene-4-butyryloxy-3-pyrrolin-2-one (producedaccording to Example 8) was suspended in 467 ml of toluene andhydrogenated for 28 hours with 4.67 g of palladium/activated carbon (5percent of Pd) in an autoclave at room temperature and 2 MPa (20 bar).Then the catalyst was filtered off and the filtrate was concentrated byevaporation in a vacuum. The residue was recrystallized from diisopropylether. The yield of the title compound was 32.88 percent (69 percent oftheory). The title compound had a melting point of 85.6° to 87° C. Otherdata concerning the title compound was:

¹ H-NMR (CDCl₃, 400 MHz): 0.98 (t, J=7.3, 3H), 1.69 (sext., J=7.3, 2H),2.34-2.41 (m, 3H), 2.68-2.77 (m, 2H), 2.92 (dd, J=14.0, 5.1, 1H),4.07-4.18 (m, 1H), 5.40-5.48 (m, 1H), 6.04 (br.s, 1H), 7.16-7.34 (m,5H).

EXAMPLE 10 (4S,5S)-5-Benzyl-4-butyryloxypyrrolidin-2-one (Vb, R¹=phenyl, R² =propyl)

In a two-phase system of 145 ml of water and 36 ml of toluene, 21.14 gof (4RS,5RS)-5-benzyl-4-butyryloxypyrrolidin-2-one (produced accordingto Example 9) and 4.22 g of Candida cylindracea lipase (Biocatalysts)were reacted analogously to Example 5. After 116 hours and theconsumption of 47.01 ml of 1M sodium hydroxide solution (correspondingto 58 percent conversion), the reaction was terminated. The reactionmixture was diluted with 600 ml of toluene and 250 ml of water andstirred vigorously for 30 minutes. The phases were separated and theaqueous phase was extracted with 300 ml of toluene. The combined toluenephases were concentrated by evaporation in a vacuum, the residue wastaken up in 170 ml of toluene, washed three times with 40 ml of watereach and again concentrated by evaporation in a vacuum. Thethus-obtained crude product was recrystallized from diisopropyl ether.The yield of the title compound was 7.80 g (74 percent relative to oneenantiomer). The title compound had a melting point of 78.9° to 79.2° C.Other data concerning the title compound was:

[α]_(D) ²⁰ : -89.0° (c=1.0; CHCl₃)

EXAMPLE 11(3S,4S)-4-(tert-Butoxycarbonyamino)-3-hydroxy-5-phenylpentanoic acid (I,R¹ =phenyl, X=tert-butoxycarbonyl)

1.0 g of (4S,5S)-5-benzyl-4-butyryloxypyrrolidin-2-one (producedaccording to Example 10) was stirred for 20 hours at 80° C. in 10 ml of48 percent aqueous hydrobromic acid. The mixture was then cooled to roomtemperature, diluted with 10 ml of water and extracted three times with20 ml of diethyl ether each for removal of the butyric acid. The etherphase was discarded. The aqueous phase was cooled to -5° C. and adjustedto pH 10 with 33 percent sodium hydroxide solution. Then 20 ml oftetrahydrofuran and 0.86 g of di-tert-butyl dicarbonate were added andthe mixture was brought to reaction for 24 hours at room temperature anda constant pH of 10. Then the mixture was acidified with 1M hydrochloricacid to pH 1 and extracted three times with 50 ml of diethyl ether each.The combined ether phases were dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate/acetic acid10:10:0.25). The yield of the title compound was 0.64 g (54 percent oftheory). The title compound had a melting point of 153.2° to 153.4° C.(CHCl₃ /hexane). Other data concerning the title compound was:

[α]_(D) ²⁰ : -37.7° (c=1.1; CH₃ OH)

¹ H-NMR (CDCl₃, 60° C.; 400 MHz): 1.40 (s, 9H) 2.40-2.66 (m, 2H)2.86-2.96 (m, 2H) 3.66-3.82 (m, 1H) 3.96-4.07 (m, 1H) 4.82-5.00 (br.s,1H) 7.12-7.35 (m, 5H)

EXAMPLE 12 (4S,5S)-4-Butyryloxy-5-(cyclohexylmethyl)pyrrolidin-2-one(Vb, R¹ =cyclohexyl, R² =propyl

1.0 g of (4S,5S)-5-benzyl-4-butyryloxypyrrolidin-2-one (producedaccording to Example 10) was dissolved in 10 ml of ethyl acetate, mixedwith 100 mg of rhodium/activated carbon (5 percent of Rh, JohnsonMatthey Type 20A) and hydrogenated for 20 hours in an autoclave at roomtemperature at 2 MPa (20 bar). Then the catalyst was filtered off andthe filtrate was concentrated by evaporation in a vacuum. The yield ofthe title compound was 1.0 g of viscous oil (about 98 percent). Otherdata concerning the title compound was:

¹ H-NMR (CDCl₃, 300 MHz): 0.8-1.35 (m, 9H) 1.45 (t, 2H) 1.58-1.80 (m,7H) 2.22-2.40 (m, 3H) 2.70 (dd, 1H) 3.85-3.98 (m, 1H) 5.35-5.45 (m, 1H)6.35 (br.s, 1H)

What is claimed is:
 1. Process for the production of optically-active(rel-3R,4R)-4-amino-3-hydroxycarboxylic acids of formula: ##STR15##wherein R¹ is a branched alkyl group having 1 to 10 C atoms, a straightchain alkyl group having 1 to 10 carbon atoms, an alkyl group having 1to 10 carbon atoms containing at least one substituent, an aryl group,an arylalkyl group, a cycloalkyl group, a substituted arylalkyl group, asubstituted aryl group and a substituted cycloalkyl group, and X ishydrogen, comprising (i) acylating a substituted tetramic acid offormula: ##STR16## wherein R¹ has the above-mentioned meaning, with acarboxylic acid or a carboxylic acid derivative of formula: ##STR17##wherein R² is a branched alkyl group having 1 to 10 C atoms, a straightchain alkyl group having 1 to 10 carbon atoms, an alkyl group having 1to 10 carbon atoms containing at least one substituent and an arylgroup, and Y is halogen, OH or OC(═O)R², to a compound of formula:##STR18## wherein R¹ and R² have the above-mentioned meaning, (ii)stereoselectively hydrogenating the compound of formula I to thecorresponding enantiomeric pyrrolidin-2-ones of formula: ##STR19##wherein R¹ and R² have the above-mentioned meanings, with a catalyst ofthe group consisting of palladium catalyst, rhodium catalyst andpalladium/rhodium catalyst, (iii) hydrolyzing enantioselectively the(4R,5R)-enantiomer (Va) with a lipase from Candida cylindracea to thecorresponding (4R,5R)-4-hydroxypyrrolidin-2-one of formula: ##STR20##(iv) separating hydroxy compound VI from the nonhydrolyzed(4S,5S)-enantiomer (Vb), and (v) hydrolyzing with cleavage of the lactamring of the acyloxy compound Vb or the hydroxy compound VI to the endcompound I.
 2. The process according to claim 1 wherein butyric acid orbutyryl chloride is used as the carboxylic acid or carboxylic acidderivative (III), respectively.
 3. The process according to claim 2wherein butyryl chloride is used as the butyric acid derivative.
 4. Theprocess according to claim 1 wherein a supported palladium catalyst isused as the catalyst.
 5. The process according to claim 1 wherein, afterthe enantioselective hydrolysis, the nonhydrolyzed (4S,5S)-enantiomer(Vb) is hydrolyzed with cleavage of the lactam ring to the end compoundI.
 6. The process according to claim 5 wherein a 5-idobutylidenetetramicacid (R¹ =isopropyl) or 5-benzylidenetetramic acid (R¹ =phenyl) is usedas the substituted tetramic acid (II).
 7. The process according to claim1 wherein, after the enantioselective hydrolysis, the nonhydrolyzed(4S,5S)-enantiomer (Vb) is hydrolyzed with cleavage of the lactam ringto the end compound I.
 8. The process according to claim 1 wherein a5-isobutylidenetetramic acid (R¹ =isopropyl) or 5-benzylidenetetramicacid (R¹ =phenyl) is used as the substituted tetramic acid (II).
 9. Theprocess according to claim 1 wherein the acyloxy compound Vb ishydrolyzed with cleavage of the lactam ring to the end compound I. 10.The process according to claim 1 wherein the hydroxyl compound VI ishydrolyzed with cleavage of the lactam ring to the end compound I. 11.Process for the production of optically-active(rel-3R,4R)-4-amino-3-hydroxycarboxylic acids of formula: ##STR21##wherein R¹ is a branched alkyl group having 1 to 10 C atoms, a straightchain alkyl group having 1 to 10 carbon atoms, an alkyl group having 1to 10 carbon atoms containing at least one substituent, an aryl group,an arylalkyl group, a cycloalkyl group, a substituted arylalkyl group, asubstituted aryl group and a substituted cycloalkyl group, and Q is anamino protective group, comprising (i) acylating a substituted tetramicacid formula: ##STR22## wherein R¹ has the above-mentioned meaning, witha carboxylic acid or a carboxylic acid derivative of formula: ##STR23##wherein R² is a branched alkyl group having 1 to 10 C atoms, a straightchain alkyl group having 1 to 10 carbon atoms, an alkyl group having 1to 10 carbon atoms containing at least one substituent and an arylgroup, and Y is halogen, OH or OC(═O)R², to a compound of formula:##STR24## wherein R¹ and R² have the above-mentioned meanings, with acatalyst of the group consisting of palladium catalyst, rhodium catalystand palladium/rhodium catalyst, (iii) stereoselectively hydrogenatingthe compound of formula I to the corresponding enantiomericpyrrolidin-2-ones of formula: ##STR25## wherein R¹ and R² have theabove-mentioned meanings, with a catalyst of the group consisting ofpalladium catalyst, rhodium catalyst and palladium/rhodium catalyst,(iii) hydrolyzing enantioselectively the (4R,5R)-enantiomer (Va) with alipase from Candida cylindracea to the corresponding(4R,5R)-4-hydroxypyrrolidin-2-one of formula: ##STR26## (iv) separatinghydroxy compound VI from the nonhydrolyzed (4S,5S)-enantiomer (Vb), (V)hydrolyzing with cleavage of the lactam ring of the acyloxy compound Vbor the hydroxy compound VI to optically-active(rel-3R,4R)-4-amino-3-hydroxycarboxylic acids of general formula:##STR27## wherein R¹ has the above-mentioned meaning, and X is hydrogen,and (vi) converting compound I to end product compound VII.